Bis-aryl amide compounds and methods of use

Abstract

The present invention comprises a new class of compounds useful for the prophylaxis and treatment of protein kinase mediated diseases, including autoimmune disease and inflammation. In one embodiment, the compounds have a general Formula I wherein A 1 , A 2 , A 3 , A 4 , L, R 1 , R 2 and R 3 are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of the present invention, methods of use such as treatment of Lck and/or c-Kit kinase mediated diseases by administering the compounds of the invention, or compositions including one or more compounds of the invention, and intermediates and processes useful for the preparation of compounds of the present invention.

What is claimed is: 
     
       1. A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein
 A 1  is CR 4 ; 
 A 2  is CR 5 ; 
 A 3  is CR 6 ; 
 A 4  is CR 7 ; provided that when L is —NHC(O)—, A 1  is CR 4 , A 2  is CR 5 , A 3  is CR 6  and A 4  is CR 7 , then R 6  is H; 
 L is —C(O)NR 7 — or —NR 7 C(O)—; 
 R 1  is quinolinyl or isoquinolinyl, each ring of which is optionally substituted independently with 1-3 substituents of R 8 , R 9 , NR 8 R 8 , NR 8 R 9 , OR 8 , OR 9 , SR 8 , SR 9 , C(O)R 8 , C(O)R 9 , OC(O)R 8 , C(O)OR 8 , C(O)NR 8 R 8 , C(O)NR 8 R 9 , NR 8 C(O)R 8 , NR 8 C(O)R 9 , NR 8 C(O)NR 8 R 8 , NR 8 C(O)NR 8 R 9 , NR 8 C(O)OR 8 , NR 8 C(O)OR 9 , S(O) 2 R 8 , S(O) 2 R 9 , S(O) 2 NR 8 R 8 , S(O) 2 NR 8 R 9 , NR 8 S(O) 2 NR 8 R 8 , NR 8 S(O) 2 NR 8 R 9 , NR 8 S(O) 2 R 8  or NR 8 S(O) 2 R 9 ; 
 R 2  is H, C 1-10 -alkyl, C 2-10 -alkenyl or C 2-10 -alkynyl, each of the C 1-10 -alkyl, C 2-10 -alkenyl and C 2-10 -alkynyl optionally comprising 1-3 heteroatoms selected from N, O and S and optionally substituted with 1-3 substituents of R 9  or R 10 ; 
 R 3  is a ring selected from phenyl and benzo[1.3]dioxolyl wherein said ring is optionally substituted independently with 1-5 substituents of R 11 , R 12 , R 13 , NR 11 R 11 , NR 11 R 12 , OR 11 , SR 11 , OR 12 , SR 12 , C(O)R 11 , C(S)R 11 , CN(CN)R 11 , C(O)R 12 , C(S)R 12 , CN(CN)R 12 , C(O)C(O)R 11 , OC(O)R 11 , COOR 11 , C(O)SR 11 , C(O)C(O)R 12 , OC(O)R 12 , COOR 12 , C(O)SR 12 , C(O)NR 11 R 11 , C(S)NR 11 R 11 , C(O)NR 11 R 12 , C(S)NR 11 R 12 , OC(O)NR 11 R 12 , NR 11 C(O)R 11 , NR 11 C(O)R 12 , NR 11 C(S)NR 11 C(S)R 12 , NR 11 C(O)NR 11 R 11 , NR 11 C(O)NR 11 R 12 , NR 11 C(S)NR 11 R 11 , NR 11 C(S)NR 11 R 12 , NR 11 C(O)OR 11 , NR 11 C(O)OR 12 , NR 11 C(O)C(O)R 11 , NR 11 C(O)C(O)R 12 , NR 11 C(O)C(O)NR 11 R 12 , S(O) 2 R 11 , S(O) 2 R 12 , S(O) 2 NR 11 R 11 , S(O) 2 NR 11 R 12 , NR 11 S(O) 2 NR 11 R 12 , NR 11 S(O) 2 R 11  or NR 11 S(O) 2 R 12 ; 
 R 4  is H or C 1-10 -alkyl; 
 R 5  is H; 
 R 6  is H; 
 R 7  is H; 
 R 8  is H, halo, haloalkyl, CN, NO 2 , acetyl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl or C 3-10 -cycloalkyl, each of the C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl and C 3-10 -cycloalkyl optionally comprising 1-4 heteroatoms selected from N, O and S and optionally substituted with 1-3 substituents of NR 8 R 9 , NR 9 R 9 , OR 8 , SR 8 , OR 9 , SR 9 , C(O)R 8 , OC(O)R 8 , COOR 8 , C(O)R 9 , OC(O)R 9 , COOR 9 , C(O)NR 8 R 9 , C(O)NR 9 R 9 , NR 9 C(O)R 8 , NR 9 C(O)R 9 , NR 9 C(O)NR 8 R 9 , NR 9 C(O)NR 9 R 9 , NR 9 (COOR 8 ), NR 9 (COOR 9 ), OC(O)NR 8 R 9 , OC(O)NR 9 R 9 , S(O) 2 R 8 , S(O) 2 NR 8 R 9 , S(O) 2 R 9 , S(O) 2 NR 9 R 9 , NR 9 S(O) 2 NR 8 R 9 , NR 9 S(O) 2 NR 9 R 9 , NR 9 S(O) 2 R 8 , NR 9 S(O) 2 R 9  or R 9 ; 
 R 9  is a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and wherein each ring of said ring system is optionally substituted independently with 1-3 substituents of R 10 , oxo, NR 10 R 10 , OR 10 , SR 10 , C(O)R 10 , COOR 10 , C(O)NR 10 R 10 , NR 10 C(O)R 10 , NR 10 C(O)NR 10 R 10 , S(O) 2 R 10 , S(O) 2 NR 10 R 10  or NR 10 S(O) 2 R 10 ; 
 R 10  is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein each of the C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl and ring of said ring system is optionally substituted independently with 1-3 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl; 
 R 11  is H, halo, haloalkyl, CN, NO 2 , acetyl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl or C 3-10 -cycloalkyl, each of the C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl and C 3-10 -cycloalkyl optionally comprising 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents of NR 12 R 13 , NR 13 R 13 , OR 12 , SR 12 , OR 13 , SR 13 , C(O)R 12 , OC(O)R 12 , COOR 12 , C(O)R 13 , OC(O)R 13 , COOR 13 , C(O)NR 12 R 13 , C(O)NR 13 R 13 , NR 13 C(O)R 12 , NR 13 C(O)R 13 , NR 13 C(O)NR 12 R 13 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)OR 12 , NR 13 C(O)OR 13 , OC(O)NR 12 R 13 , OC(O)NR 13 R 13 , S(O) 2 R 12 , S(O) 2 NR 12 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 12 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 12 , NR 13 S(O) 2 R 13  or R 13 ; 
 R 12  is a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and wherein each ring of said ring system is optionally substituted independently with 1-3 substituents of R 13 , oxo, NR 13 R 13 , OR 13 , SR 13 , C(O)R 13 , COOR 13 , C(O)NR 13 R 13 , NR 13 C(O)R 13 , NR 13 C(O)NR 13 R 13 , OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13  or NR 13 S(O) 2 R 13 ; 
 alternatively, R 11  and R 12  taken together form a partially or fully saturated or unsaturated 5-6 membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and the ring optionally substituted independently with 1-5 substituents of R 13 ; and 
 R 13  is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, oxo, acetyl, benzyl, cyclopropyl, cyclobutyl or a partially or fully saturated or unsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, and optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, benzyl or phenyl. 
 
     
     
       2. The compound of  claim 1  wherein R 1  is 
       
         
           
           
               
               
           
         
       
       said ring optionally substituted independently with 1-3 substituents of R 8 , R 9 , NR 8 R 8 , NR 8 R 9 , OR 8 , OR 9 , SR 8 , SR 9 , C(O)R 8 , C(O)R 9 , OC(O)R 8 , C(O)OR 8 , C(O)NR 8 R 8 , C(O)NR 8 R 9 , NR 8 C(O)R 8 , NR 8 C(O)R 9 , NR 8 C(O)NR 8 R 8 , NR 8 C(O)NR 8 R 9 , NR 8 C(O)OR 8 , NR 8 C(O)OR 9 , S(O) 2 R 8 , S(O) 2 R 9 , S(O) 2 NR 8 R 8 , S(O) 2 NR 8 R 9 , NR 8 S(O) 2 NR 8 R 8 , NR 8 S(O) 2 NR 8 R 9 , NR 8 S(O) 2 R 8  or NR 8 S(O) 2 R 9 . 
     
     
       3. The compound of  claim 1  wherein
 A 1  is CR 4 , wherein R 4  is C 1-10 -alkyl; 
 A 2  is CH; 
 A 3  is CH; and 
 A 4  is CH. 
 
     
     
       4. The compound of  claim 1  wherein
 R 1  is quinolinyl or isoquinolinyl; and 
 R 2  is H or C 1-10 -alkyl. 
 
     
     
       5. The compound of  claim 1  wherein R 3  is phenyl optionally substituted as defined in  claim 1 . 
     
     
       6. The compound of any of  claim 1 , or a pharmaceutically acceptable salt thereof, selected from:
 N3-(6,7-dimethoxyquinolin-3-yl)-4-methyl-N1-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)isophthalamide; 
 N-(3-((6,7-dimethoxyquinolin-3-yl)carbamoyl)-4-methylphenyl)-2-methyl-3-(trifluoromethyl)benzamide; 
 N-(3-((6,7-dimethoxyquinolin-3-yl)carbamoyl)-4-methylphenyl)-2,2-difluorobenzo[d][1,3]dioxole-4-carboxamide; 
 N-(3-((6,7-dimethoxyquinolin-3-yl)carbamoyl)-4-methylphenyl)-2,2-difluorobenzo[d][1,3]dioxole-5-carboxamide; 
 N3-(6,7-dimethoxyquinolin-3-yl)-N1-(2-fluoro-5-(trifluoromethyl)phenyl)-4-methylisophthalamide; 
 2-chloro-N-(3-((6,7-dimethoxyquinolin-3-yl)carbamoyl)-4-methylphenyl)-3-(trifluoromethyl)benzamide; 
 N-(3-((6,7-dimethoxyquinolin-3-yl)carbamoyl)-4-ethylphenyl)-2-methyl-3-(trifluoromethyl)benzamide; 
 4-methyl-N3-(quinolin-3-yl)-N1-(3-(trifluoromethyl)phenyl)isophthalamide; 
 4-methyl-N1-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-N3-(quinolin-3-yl)isophthalamide; 
 N-(4-methyl-3-((2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)carbamoyl)phenyl)quinoline-4-carboxamide; 
 N1-(2-fluoro-5-(trifluoromethyl)phenyl)-4-methyl-N3-(quinolin-3-yl)isophthalamide; and 
 5-(isoquinolin-1-ylamino)-2-methyl-N-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)benzamide. 
 
     
     
       7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to  claim 1 .